Drug addiction is a widespread condition affecting 8-10% of the population nationwide. Although men and women exhibit similar rates of addiction, there are remarkable sex differences in the development of this condition. In fact, women progress more rapidly through the stages of addiction for several abused drugs, including psychostimulants. It is becoming apparent that the ovarian hormone, estradiol, plays an important role in the etiology of drug addiction in females. Surprisingly few studies have attempted to characterize the neurobiological mechanisms underlying the impact of estradiol on drug addiction. We know that in females, estradiol influences the nucleus accumbens (NAc), a brain region important for the expression of neuroanatomical and behavioral hallmarks of drug addiction. In our attempt to elucidate these underlying mechanisms we demonstrated that estradiol 1) induces synaptic plasticity in medium spiny neurons (MSNs) of the female NAc and 2) potentiates behavioral sensitization to psychostimulants. Further, we recently demonstrated that both of these effects of estradiol are dependent on metabotropic glutamate receptor type 5 (mGluR5) and the type 1 cannabinoid receptor (CB1r). I integrated previous findings that estradiol activates membrane- localized estrogen receptors that are functionally coupled to mGluR5 in female MSNs, along with observations that postsynaptic activation of mGluR5 stimulates synthesis and release of endogenous cannabinoids (endoCBs) to develop the novel hypothesis that estradiol, mGluR5 and CB1r act through one continuous signaling pathway within the female rat NAc. Specific Aim 1 is designed to test this novel mechanism using an innovative in vivo physiological approach with the goal of demonstrating that estradiol induced changes in endoCB release are mediated via mGluR5 signaling. As the cannabinoid system is emerging as a key neurochemical mediator of drug- related plasticity and behavior, elucidating this mechanism may provide fundamental information in understanding how estradiol enhances female sensitivity to drugs of abuse.